臺灣博碩士論文加值系統

結直腸癌（Colorectal cancer, CRC）及肝細胞癌（Hepatocellular carcinoma, HCC）是全球最主要癌症死亡的原因，目前針對晚期結直腸癌及肝細胞癌，有幾種標靶藥物，但臨床預後仍然不佳，因此，仍須開發更多癌症標靶藥物。
自噬通量的增加通常會促進腫瘤細胞的存活與生長。自噬相關蛋白ATG4會切割LC3，促進自噬體的形成。ATG4的所有亞型中 (ATG4A、ATG4B、ATG4C和ATG4D），ATG4B具有最廣泛的作用。其他文獻表明ATG4B在某些癌症類型中的表達上升。根據實驗室先前的研究，ATG4B抑制胜肽TAT-GBRL2H2除可以抑制癌細胞內的自噬活性，也會抑制癌細胞活力，並有效降低細胞自噬活性，本研究中主要在探討融合胜肽TAT-GBRL2H2對癌細胞自噬途徑的下游活性氧類累積及細胞死亡。
本研究中，我利用CellTiter Glo評估了TAT-GBRL2H2處理的HCC及CRC細胞的細胞活力。使用流式細胞儀測定檢測 TAT-GBRL2H2 對 CRC 和HCC 細胞的autophagy-related protein 4B (ATG4B) 與其受質 LC3B 蛋白質結合抑制、活性氧化物質產生及鈣內流的情形。也透過螢光染色、CellTiter Glo 3D觀察胜肽對癌細胞球體形成的影響。利用細胞侵襲試驗確認TAT-GBRL2H2對癌細胞侵襲能力的影響。
實驗結果指出，TAT-GBRL2H2胜肽會抑制ATG4B與LC3B的結合，且TAT-GBRL2H2胜肽在癌細胞中也表現出抑制細胞活性的效果。在球體形成試驗中，處理TAT-GBRL2H2胜肽也會使球體細胞死亡比例增加，TAT-GBRL2H2胜肽亦會減少癌細胞的侵襲作用。此外，使用活性氧清除劑預處理，對 TAT-GBRL2H2 胜肽殺死的CRC細胞具有增加死亡之效果，表示其誘導的活性氧為細胞存活的路徑分子。TAT-GBRL2H2胜肽也會增加癌細胞中鈣累積，並進一步促進細胞死亡，顯示TAT-GBRL2H2胜肽抑癌的效果可能與鈣離子上升有關。
根據我的研究結果，TAT-GBRL2H2胜肽抑制了癌細胞的生長，這表示其具有開發針對ATG4B過表達癌症的胜肽治劑的潛力。

Colorectal cancer (CRC) and hepatocellular carcinoma (HCC) are leading causes of cancer-related mortality globally. Several targeted therapies are currently available for advanced CRC and HCC. However, clinical outcomes remain poor. Therefore, there is still a need to develop more targeted therapies for cancer.
Increasing autophagic flux typically promotes the survival and growth of tumor cells. The autophagy-related protein ATG4 cleaves LC3, facilitating the formation of autophagosomes. Among all ATG4 subtypes (ATG4A, ATG4B, ATG4C, and ATG4D) , ATG4B has the most extensive functions. Other literature indicates that the expression of ATG4B is elevated in certain cancer types. According to previous laboratory studies, the synthetic ATG4B inhibitory peptide TAT-GBRL2H2 not only suppresses autophagic activity within cancer cells but also inhibits their viability, effectively reducing cellular autophagy. Our previous results have shown that the TAT-GBRL2H2 peptide inhibits cancer cell viability and effectively reduces cellular autophagic activity. Therefore, this study primarily explores the downstream effects of the TAT – GBRL2H2 peptide on reactive oxygen species (ROS) accumulation and cell death via cancer cell autophagy pathways.
In this study, I used CellTiter Glo to evaluate the cell viability of CRC and HCC cells treated with TAT-GBRL2H2. Flow cytometry was employed to assess the effect of TAT-GBRL2H2 on the binding of autophagy-related protein 4B (ATG4B) to its substrate LC3B, on the generation of reactive oxygen species and calcium influx in CRC and HCC cells. Additionally, I used fluorescence staining and 3D CellTiter Glo to observe the impact of the peptide on the formation of cancer cell spheroids. A transwell assay was used to confirm the effect of TAT-GBRL2H2 on the invasive ability of cancer cells.
Our results indicate that the TAT-GBRL2H2 peptide inhibits the binding of ATG4B to LC3B and shows an inhibitory effect on cell viability in cancer cells. In spheroid formation assays, treatment with TAT-GBRL2H2 peptide increased the proportion of spheroid cell death and reduced cancer cell invasion. Additionally, pre-treatment with reactive oxygen species scavenger induced the cytotoxic effect of TAT-GBRL2H2 peptide on CRC cells, indicating that induced reactive oxygen species serve as signaling molecules for cell survival. The TAT-GBRL2H2 peptide also increased calcium accumulation in cancer cells, further inducing cell death, suggesting that the anti-cancer effects of TAT-GBRL2H2 peptide may be associated with calcium ion elevation.
Based on our research findings, the TAT-GBRL2H2 peptide inhibits cancer cell growth, suggesting its potential for development as a peptide-based therapeutic agent targeting cancers with overexpression of ATG4B.

目錄
論文審定書 i
中文摘要 ii
英文摘要 iv
目錄 vi
圖次 ix
縮寫表 xi
第一章 前言 1
1.1結直腸癌 (Colorectal cancer, CRC) 1
1.2肝細胞癌（Hepatocellular carcinoma, HCC） 2
1.3細胞自噬 (Autophagy) 4
1.4自噬因子 ATG4B (Autophagy-related gene 4B) 與ATG8 (LC3) 6
1.5 胜肽藥物 (Peptide drug) 7
1.6 研究目的 10
第二章 材料與方法 12
2.1胜肽設計 12
2.2藥品配製 12
2.3細胞培養 (Cell culture) 16
2.4細胞存活率試驗 (Cell Viability Assay) 19
2.5雙分子螢光互補測定 (Bimolecular Fluorescence Complementation Assay) 20
2.6活性氧化物質產生試驗 (Reactive oxygen species Production) 21
2.7鈣離子流量試驗 (Calcium Flux) 22
2.8細胞侵襲試驗 (Transwell cell invasion assay) 24
2.9癌細胞球體形成試驗 (Sphere formation assay) 25
2.10球體細胞存活率試驗 (3D sphere cell viability assay) 25
2.11活/死細胞螢光試驗 (Live/Dead cytotoxicity assay) 26
2.12統計分析 26
第三章 實驗結果 27
3.1胜肽對細胞中ATG4B及LC3結合的抑制作用 27
3.2胜肽對癌細胞活性的作用 27
3.3胜肽對癌細胞球體形成能力的影響 28
3.4胜肽對癌細胞中活性氧化物產生之影響 29
3.5胜肽對癌細胞中鈣離子累積之影響 30
3.6胜肽對癌細胞死亡路徑的影響 30
3.7胜肽抑制癌細胞侵襲的能力 31
第四章 討論 32
第五章 結論 36
第六章 實驗結果圖 37
第七章 附錄 47
參考文獻 48

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